Platelets play critical roles in hemostasis and its pathophysiology. Undesired platelet activation is a result of many common pathologies, e.g., hypertension and arteriosclerosis, and leads to excessive platelet aggregation and the generation of occlusive thrombi (thrombosis). The ischemic events that follow, such as myocardial infarction and stroke, are leading causes of death in the developed world
Antithrombotics are used in patients who are at increased risk of clotting, typically because of surgery, major trauma, vascular diseases, or blood clotting abnormalities. There are two major classes of antithrombotics: classical anticoagulants (e.g., heparin and warfarin), which interfere with the plasma clotting system, and antiplatelet drugs, which act by reducing the ability of platelets to aggregate. The anticoagulants are the preferred treatment of venous thrombosis, and antiplatelet drugs are preferred for arterial thrombosis. The two groups are less commonly used in combination, because of increased risk of major blood homeostasis compromise. The antiplatelet drugs have proven to be the safer group, especially for prophylactic and long term use.
The most popular group of antiplatelet agents is the group of thienopyridines, which irreversibly inhibits the platelet P2Y12 receptor. The most successful of this group, clopidogrel (Plavix®), alone or in addition to aspirin, has proven to be safe and moderately effective in reducing the composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or stroke in patients with coronary syndromes (Yusuf et al. N. Engl. J. Med. 2001, 345:494-502; Savi and Herbert Semin. Thromb. Hemost. 2005, 31:174-83). Notwithstanding its widespread use, clopidogrel has important drawbacks. It is a prodrug, which has to be metabolized by two separate cytochrome P450 enzymes in the liver to produce the active substance. This causes a delay of action and necessitates “preloading” patients before a procedure and also results in significant inter-patient activity variability due to variations in the P450 system and liver function. Limited response to clopidogrel, often referred to as “clopidogrel resistance,” occurs in up to 20% of patients. The requirement for liver metabolism also increases the potential for drug-drug interactions. The active metabolite of clopidogrel irreversibly inhibits P2Y12 platelet receptors, and its antithrombotic activity persists long after administration of the drug. The prolonged effect can be problematic, for example when urgent surgery is required, because of an increased risk for bleeding.
In the search for fast acting and reversible antiplatelet agents the adenosine triphosphate (ATP) scaffold has been extensively modified, which led to the development of the drug candidate Cangrelor, which is presently in advanced clinical development. An orally available adenosine analog related to Cangrelor, AZD 6140, is also in late stage clinical trials.
Bis-adenosine tetraphosphate (Ap4A), like ATP, possesses weak antiplatelet activity. Yet, very few Ap4A analogs have been prepared and studied as possible antiplatelet agents. Bis-adenosine P2,P3-methylene-, and halomethylenetetraphosphates, and bis-adenosine P1,P4-dithio-P2,P3-monochloromethylenetetraphosphate have been disclosed as antiplatelet and antithrombotic agents in U.S. Pat. No. 5,049,550, and U.S. Pat. No. 5,681,823, respectively, albeit with activity insufficient for clinical development. Thus, there is a need for new diadenosine tetraphosphates and related analogs.